Cisplatin–Protein Interactions: Unexpected Drug Binding to N-Terminal Amine and Lysine Side Chains

Abstract

Literature studies carried out by mass spectrometry and X-ray crystallography have demonstrated that cisplatin is able to bind proteins mainly close to Met, His, and free Cys side chains. To identify possible alternative modes of cisplatin binding to proteins at the molecular level, here we have solved the high-resolution X-ray structure of the adduct formed in the reaction between the drug and the model protein thaumatin, which does not contain any His and free Cys residues and possesses just one buried Met. Our data reveal unexpected cisplatin binding sites on the protein surface that could have general significance: cisplatin fragments -[Pt(NH3)2Cl](+), -[Pt(NH3)Cl2], and -[Pt(NH3)2(OH2)](2+) bind to a protein N-terminus and close to Lys and Glu side chains.

Role of the Metal Center in the Modulation of the Aggregation Process of Amyloid Model Systems by Square Planar Complexes Bearing 2-(2′-pyridyl)benzimidazole Ligands

“…Considering the preference of Pt compounds for specific amino acid residues [40,41], the sequence of the peptide and the finding that the Pt fragment binds both monomeric and dimeric forms of NPM1 264-277, it can be surmised that the most probable Pt binding sites are the side chains of lysine residues in positions 4 and 10 and of Glu in position 2. These residues were already found as ligands of Pt complexes [40,42,43].…”

X-ray Structure of the Carboplatin-Loaded Apo-Ferritin Nanocage

“…Interestingly, the electron density close to the His132 side chain and close to the other conformation of the His49 side chain is reminiscent of that observed in the X-ray structure of the adduct formed in the reaction between hen egg white lysozyme and CBDCA. , It is also interesting to note that CBDCA binding to His side chains has already been observed in the crystal structure of the adduct that the drug forms with RNase A . His side chains have been also found frequently in the adduct that cisplatin and other Pt-based drugs form with proteins. − …”

Elucidating Role of Reactive Oxygen Species (ROS) in Cisplatin Chemotherapy: A Focus on Molecular Pathways and Possible Therapeutic Strategies

“…As an electrophilic reagent, platinum can interact with nucleophilic residues of nucleobases, including guanine and adenosine by forming covalent bonds. Due to the presence of nucleophilic residues on a wide variety of cellular components, platinum-containing compounds can interact with ribosomes, spliceosomes, RNA and proteins [14][15][16][17]. The major pathway for suppressing cancer progression by CP is inducing DNA damage by forming adducts with DNA, resulting in apoptosis and cell cycle arrest [18].…”